Anisotropic Microgels by Supramolecular Assembly and Precipitation Polymerization of Pyrazole‐Modified Monomers

Abstract Soft colloidal macromolecular structures with programmable chemical functionalities, size, and shape are important building blocks for the fabrication of catalyst systems and adaptive biomaterials for tissue engineering. However, the development of the easy upscalable and template‐free synthesis methods to obtain such colloids lack in understanding of molecular interactions that occur in the formation mechanisms of polymer colloids. Herein, a computer simulation‐driven experimental synthesis approach based on the supramolecular self‐assembly followed by polymerization of tailored pyrazole‐modified monomers is developed. Simulations for a series of pyrazole‐modified monomers with different numbers of pyrazole groups, different length and polarity of spacers between pyrazole groups and the polymerizable group are first performed. Based on simulations, monomers able to undergo π–π stacking and guide the formation of supramolecular bonds between polymer segments are synthesized and these are used in precipitation polymerization to synthesize anisotropic microgels. This study demonstrates that microgel morphologies can be tuned from spherical, raspberry‐like to dumbbell‐like by the increase of the pyrazole‐modified monomer loading, which is concentrated at periphery of growing microgels. Combining experimental and simulation results, this work provides a quantitative and predictive approach for guiding microgel design that can be further extended to a diversity of colloidal systems and soft materials with superior properties.

dissolving 20.0 g of 2-chloroethylamine (172.0 mmol) in MeCN (60 mL). The suspension was cooled to 0 °C and triethylamine (TEA, 23.8 mL, 172.0 mmol) was added dropwise over 30 min. The reaction stirred for 1 h at 0 °C. Afterwards, the white precipitate was removed by filtration and the desired fluid was obtained (yield = 100 %). In the next step, pyrazole (3.00 g, 44.1 mmol) was dissolved in MeCN (60 mL). Sodium hydroxide (5.29 g, 132.3 mmol) was added to this solution, which was then stirred for 30 min at room temperature. The reaction mixture was heated up to 75 °C and the acetonitrile fluid of 2-chloroethyl amine (88.2 mmol) was added dropwise over 30 min. Then, the solution was stirred at 75 °C overnight and after that, the solution was allowed to cool down to room temperature. The formed precipitate was removed by filtration and the solvent was removed via rotary evaporation. Finally, the product was condensed at 50 °C under high vacuum to remove residues resulting in a colorless oil (4.57 g, 92 %).

Synthesis of tri(1H-pyrazol-1-yl)methane (TPM)
The CH-acid substrate was synthesized according to the procedure of Reger et al. [56] The product tri(1H-pyrazol-1-yl)methane was prepared from pyrazole and chloroform. The product was obtained as a pale-yellow solid in 62 % yield.

Synthesis of 3-bromopropyl methacrylate (BrPMA)
This compound was prepared in a similar manner as PMA-S, proceeding from
After the reaction, the solvent was removed via rotary evaporation and the residue was

Synthesis of PMA-S Microgels
The microgels with various PMA-S contents in the core were synthesized using batch free radical precipitation polymerization according to Häntzschel et al. [59] VCL (amounts see Table S1) and BIS (0.285 mmol, 3 mol%) were dissolved in water (131 mL). PMA-S (amounts see Table S1) was first dissolved in methanol (2.2 vol%) and then added to the solution. The solution was purged with nitrogen for 1 h at 70 °C. Following, a solution consisting of AMPA (0.076 mmol, 0.8 mol%) and water (4 mL) was added to initiate the polymerization. Then, the mixture was stirred for 2 h at 70 °C. The obtained microgels were dialyzed against deionized water (MWCO: 12.000-14.000 Da) for 5 days.
For the microgels containing comonomer at the periphery, the synthesis was carried out according to Gau et al. using semi-batch free radical precipitation polymerization. [60] Similarly to the batch synthesis, VCL (amounts see Table S1) and BIS (0.285 mmol, 3 mol%) were dissolved in water (131 mL). Afterwards, the solution was purged with nitrogen for 1 h at 70 °C under strong stirring. For initiation, AMPA (20.6 mg, 0.076 mmol, 0.8 mol%) was dissolved in water (4 mL) and added to the reaction mixture. Subsequently, a solution of PMA-S (amounts see Table S1) and methanol (2.2 vol%) was added 3 min after the initiation.
The mixture was then stirred for 2 h at 70 °C. The same purification was performed as for the batch microgels.

Synthesis of BPMA-S Microgels
The core-shell microgels were prepared in a similar manner to the PMA-S microgels, proceeding from VCL (amounts see

Synthesis of TPMA-S Microgels
The core-shell microgels were prepared in a similar manner to the PMA-S microgels, proceeding from VCL (amounts see

Synthesis of BPMA-L Microgels
The core-shell microgels were prepared in a similar manner to the PMA-S microgels, proceeding from VCL (amounts see

Synthesis of BPMA-LP Microgels
The core-shell microgels were prepared in a similar manner to the PMA-S microgels, proceeding from VCL (amounts see     The radial distribution function (RDF) for pyrazole groups was calculated to analyze their pair formation (Figure S13). The presence of two peaks in RDF indicates triplet formation.
Such behavior appears in all TPMA monomers. The start of peak splitting can be seen in BPMA-LP and PMA-S systems. The other system formed only doublets.
In order to understand the initial stages of the microgel synthesis, we run a series of surface experiments. The hypothesis was to mimic a VCL microgel surface. Since the x-and y-box sizes are 13.5 nm and 12.1 nm, respectively, the curved microgel surface can be approximated by the flat layer of VCL oligomers. There are two types of oligomers consisting of 5 and 10 VCL monomers, which were set regularly in hexagonal order at the constant distance of 0.9 nm. One end of oligomers was fixed in space. Due to the two-thirds of VCL monomers that had reacted when BPMA residues were added we added free VLC monomers to the simulation box with the corresponding concentration. Figure S13. The radial distribution function (RDF) for pyrazole groups in the solvent system. All plots are on the same length scale and shifted by 15 correspondingly.
The pyrazole monomers were solvated in a water/methanol mixture (2.2 vol%) in the box for three different concentrations. The overall composition for solvent and surface simulations is presented in Table S20. The snapshots of the surface system's final state are presented in Figure S14. We calculate density profiles in Figure S15 that show a distribution of the components along the normal to the surface.  Aromatic monomers with one pyrazole residue wet the surface regardless of a spacer type completely ( Figure S14 and Figure S15 A-C). They incorporate into the inner structure of the surface between oligomers. This complete wetting behavior divides into two regimes. The first regime is then pyrazole monomers repeat the surface density profile and all monomers introduced in the surface media. Among such systems are PMA-S and PMA-L. Another state is typical for PMA-LP, BPMA-L, TPMA-L, and TPMA-LP. Here, the density profiles of pyrazole monomers tend to a surface boundary at low concentrations (N=120) and make a flat layer at high concentrations. In the last case, the density curve has the same shape but shifted by 1 nm from the surface center. The next type of behavior is partial wetting which we can see only in the BPMA-S system. BPMA-S monomers form a denser aggregate on the VCL surface with increasing the concentration. The last behavior type is a bad wetting of the oligomer surface by pyrazole monomers in BPMA-LP and TPMA-S systems. Monomers form an aggregate that incorporates into the water phase at a high concentration (N=360) and the density profile spreads from 1 to 9 nm with no clear peaks and the TPMA-S system stays under bad wetting conditions. On the other hand, we can see that the BPMA-LP system follows from the complete wetting at N=120 to the partial wetting at N=180 and the bad wetting at N=360, thus, all types of monomers except BPMA-LP show only one type of behavior.
Free VCL monomers locate in the pyrazole monomer phase mostly. That can be seen as small blue segments in the red pyrazole phase.